Acute, infectious diarrhea is a leading cause of disease and death in many areas of the world. In developing countries the impact of diarrheal disease is staggering. During a one year period (1977-1978) in Asia, Africa and Latin America it was estimated that three to five billion cases of diarrhea accounted for five to ten million deaths (Walsh, J. A. et al, N. Engl. J. Med. 1979; 301: 967-974).
Since their initial identification, rotaviruses have been shown to be the most important causative agents of acute gastroenteritis requiring hospitalization of infants and young children. Studies in the United States, England, Australia and Japan have demonstrated that 34% to 63% of children hospitalized with acute diarrhea had rotavirus infections. Although comprehensive studies of gastroenteritis in developing countries have only recently been undertaken, it appears that rotavirus is a pathogen of major importance (Offit, P. A. et al., Comp. Ther. 1982 8(8): 21-26).
Rotavirus-induced gastroenteritis is primarily a disease of early childhood, most commonly affecting children between 6 and 24 months of age. The peak prevalence of the disease occurs during the cooler months in temperate climates, and year-round in tropical areas. Rotavirus is transmitted from person to person by fecal-oral route with an incubation period of from one to three days. Unlike infection in the 6-month to 24-month age group, most neonates studied are asymptomatic or have only mild disease. Also, in contrast to the severe disease encountered in young children, most adult infections are mild or asymptomatic because such episodes represent reinfection generally as a result of contact with children known to be excreting rotavirus (Offit, P. A. et al, ibid.).
Rotaviruses have also been demonstrated as a cause of neonatal diarrhea in several animal species including calves, pigs, lambs and mice.
Rotaviruses, whether of bovine or primate origin, are spherical, about 70 nm in diameter, and their name is derived from their distinctive double capsid structure. Their genome is comprised of 11 segments of double-stranded RNA and a RNA polymerase (Rodger, S. M. et al., J. Clin. Microbiol. 1981; 13: 272-278; Verly, E., et al., J. Gen. Virol. 1977; 35: 583-586; Sabara, M., et al., J. of Virol., Dec. 1982, p 813-822; Clarke, Ian N., et al., Infection and Immunity, May 1982, p 492-497; Rodger, S., et al., J. of Virol., June 1979, p 839-846).
Rotaviruses of different species share common antigens capable of showing serological cross reactions. However, there exists evidence of the existence of different serotypes of rotaviruses characterized by specific surface antigens detected most readily in the serum-neutralization (SN) test. For example, an antiserum prepared against a purified virus is known to give a much higher SN titer with the homologous virus than with viruses of heterologus serotype.
Knowledge of the clinical importance of different rotavirus serotypes is presently incomplete, but there is some epidemiologic evidence that cross-immunity between serotypes in man is limited.
Human rotaviruses may be divided into two subgroups based upon differences in certain antigens in the virus core. (Kapikian, A. Z. et al Infect. Immun, 33: 415-425 (1981); Greenberg, H. et al Infec. Immun. 39: 91-99 (1983)). Subgroup 2 has been redundantly shown to be predominant in human disease. However, subgroup 2 is composed of three distinct serotypes, namely types 1, 3 and 4, which are distinguishable by serum neutralization (SN) tests (Wyatt, R. G. et al, J. Clin. Microbiol. 18: 310-317 (1983)). Serotypes 1 and 3 appear to be the most important causes of disease in humans. Studies carried out at the Childrens Hospital of Philadelphia clearly indicated that serotype 3 was the most common cause of rotavirus gastroenteritis during the 1982-83 season. Other isolates so far serotyped are of serotype 1. No serotype 2 rotavirus was observed during the above study; serotype 4 is known world-wide, but from only a few isolates.
Studies of patients who had experienced sequential infections revealed that illness caused by one serotype did not provide protection against illness caused by another serotype (Zissis, G. et al., Lancet, Jan 7, 1978, pp. 38-39).
Belgian workers also recently reported failure in efforts to immunize adult volunteers with bovine strain NCDV rotavirus (Vesikari, T., et al., Devel. Biol. Std. 53: 229-236 (1983)). In these studies only one of twenty volunteers fed with live NCDV rotavirus exhibited a rise in antibody titer detected with enzyme-linked immunosorbent assay (ELISA) to rotavirus. The same investigators then administered live NCDV rotavirus in higher titer (10.sup.8.1 TCID.sub.50) to Finnish infants (Vesikari, T. et al., Lancet, Oct. 8, 1983, pp. 807-811). Thirteen of nineteen children and infants previously seronegative by SN test developed an SN antibody rise to the homologous NCDV rotavirus. However, the only children exhibiting an increase in SN antibody titer to human rotaviruses (serotypes 1 or 2) were those who had pre-existing SN antibody titers directed against human rotavirus.